ABCA1 (ATP-binding cassette transport 1) is a protein present in mainly cell membranes in cells of a variety of organs including liver, intestinum tenue, placenta, and adrenal gland. Moreover, the ABCA1 is a member of ABC protein family which probably participates in membrane transport of various substances such as a lipid, an amino acid, a vitamin, and a sugar (see Non-patent Document 1).
Further, ABCA1 is an essential protein for a reaction that produces a high-density lipoprotein (HDL) from lipids of cells, and is also a rate-determining factor (or a rate-limiting factor) of the HDL production. The HDL production by ABCA1 is also a main releasing route of cell cholesterol including HDL. HDL is a lipid-protein complex particle produced by an action of a helical apolipoprotein (e.g., apoprotein A-I (apoAI)) that is mainly synthesized in and secreted from liver and intestinum tenue epithelial cells and protein ABCA1 present in cell membranes. HDL removes excess cholesterol from peripheral tissues in blood and transports the excess cholesterol back to the liver, which is called “reverse cholesterol transport”, and has an extremely important role in the lipid metabolism, and HDL cholesterol is sometimes called “good cholesterol”.
Moreover, the level of HDL in blood is measured as an index of the concentration of HDL cholesterol. In general, a subject having a blood HDL cholesterol level of less than 40 mg/dl is diagnosed as “hypo-high density lipoproteinemia”. This hypo-high density lipoproteinemia is often regarded as a risk factor for various diseases including arteriosclerosis, hyperlipemia, brain infarction, stroke, obesity, diabetes, and metabolic syndrome. In addition, the hypo-high density lipoproteinemia is also observed in various genetic diseases including Tangier disease. However, useful prophylactic or therapeutic agents for preventing or treating hypo-high density lipoproteinemia by acting on HDL itself have not been found, and appearance of such agents has been desired.
As described above, ABCA1 is a rate-determining factor of HDL production. Therefore, for the development of prophylactic and/or therapeutic agents for hypo-high density lipoproteinemia, various approaches to the increase of HDL production by ABCA1 have been conducted. For example, attempts to increase ABCA1 expression and activity by directly introducing a gene encoding ABCA1 to a host cell for the purpose of increasing cholesterol efflux and raising HDL concentration (see Patent Documents 1 and 2) and attempts to increase transcription and translation of ABCA1 gene by a specific substance for the purpose of modulating HDL cholesterol and triglyceride levels and enhance ABCA1 expression and activity (see Patent Document 3) are disclosed. Moreover, findings on inclusion of cholesterol into cells by a bisphenol-based probucol compound have also been obtained (see Non-patent Document 2). However, these documents do not specifically state on ABCA1 expression and prophylactic and/or therapeutic effects of hypo-high density lipoproteinemia by a probucol spiroquinone compound or a bisphenol-based probucol compound.
WO2005/67904 (Patent Document 4) discloses a prophylactic and/or therapeutic agent for hypo-high density lipoproteinemia, and the agent contains probucol spiroquinone, probucol diphenoquinone, and/or probucol bisphenol which are metabolites of probucol which is a therapeutic agent for hyperlipemia. However, it is difficult to say that these probucol compounds induce fully stable and continuous ABCA1 expression and prophylactic and/or therapeutic effects of hypo-high density lipoproteinemia. Incidentally, “Bulletin de la Societe Chimique de France” (France), 7-8(Pt. 2), 1973, p 2297-2300 (Non-patent Document 3) discloses that a dithiolane-1,3 compound having a spiro ring skeleton is obtained by a reaction of a cycloalkene-2-thione (such as cyclohexene-2-thione) and R′(R″)CN2.
[Patent Document 1] International Publication No. WO00/78971
[Patent Document 2] International Publication No. WO00/78972
[Patent Document 3] International Publication No. WO01/15676
[Patent Document 4] International Publication No. WO05/67904
[Non-patent Document 1] “Annual Review of Cell Biology” (United States), 8, 1992, p 67-113
[Non-patent Document 2] “Lipids” (United States), 29(12), 1994, p 819-823
[Non-patent Document 3] “Bulletin de la Societe Chimique de France” (France), 7-8(Pt. 2), 1973, p 2297-2300